Angiotensin II type 2 receptors have a major somatodendritic distribution in vasopressin-containing neurons in the mouse hypothalamic paraventricular nucleus

Abstract

The hypothalamic paraventricular nucleus (PVN) and angiotensin II (AngII) play critical roles in cardiovascular and neurohumoral regulation ascribed in part to vasopressin (VP) release. The AngII actions in the PVN are mediated largely through AngII type 1 (AT1) receptors. However, there is indirect evidence that the functionally elusive central AngII type 2 (AT2) receptors are also mediators of AngII signaling in the PVN. We used electron microscopic dual immunolabeling of antisera recognizing the AT2 receptor and VP to test the hypothesis that PVN neurons expressing VP are among the cellular sites where this receptor has a subcellular distribution conducive to local activation. Immunoreactivity for the AT2 receptor was detected in somatodendritic profiles, of which 60% of the somata and ~28% of the dendrites also contained VP. In comparison with somata and dendrites, axons, axon terminals, and glia less frequently contained the AT2 receptor. Somatic labeling for the AT2 receptor was often seen in the cytoplasm near the Golgi lamellae and other endomembrane structures implicated in receptor trafficking. AT2 receptor immunoreactivity in dendrites was commonly localized to cytoplasmic endomembranes, but was occasionally observed on extra-or peri-synaptic portions of the plasma membrane apposed by astrocytic processes or by unlabeled axon terminals. The labeled dendritic plasmalemmal segments containing AT2 receptors received asymmetric excitatory-type or more rarely symmetric inhibitory-type contacts from unlabeled axon terminals containing dense core vesicles, many of which are known to store neuropeptides. These results provide the first ultrastructural evidence that AT2 receptors in PVN neurons expressing vasopressin and other neuromodulators are strategically positioned for surface activation by AngII and/or intracellular trafficking. Keywords fluid homeostasis; cardiovascular regulation; neurosecretory neuronThe hypothalamic paraventricular nucleus (PVN) is a complex integrative center important for neurohumoral regulation and the maintenance of cardiovascular and body fluid homeostasis (Benarroch, 2005;Dampney et al., 2005). The vasopressin (VP)-containing neurons in the PVN are among the principal mediators of these critical functions (de Wardener, 2001). The VPCorrespondence to: Christal G. Coleman, Ph.D., Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 407 East 61st St., New York, NY 10065, E-mail: chc2021@med.cornell.edu. Section Editor: Dr. Menahem Segal Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Acc...

Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent

“…Further work is required to causally link specific RAS receptor subtypes to the AVP elevation, as morphological and functional evidence support roles for both AT 1 and AT 2 receptors in AVP release (reviewed in Ref. 10).…”

“…Two major mechanisms have been documented that account for the blood pressure effects of brain angiotensin. First, actions of the RAS within the supraoptic (SON) and paraventricular hypothalamic nuclei (PVN) stimulate the production and release of arginine vasopressin (AVP, also known as antidiuretic hormone, ADH, or argipressin) (4,10,17,31,51,53,62). Second, hindbrain and brain stem actions of the RAS alter baroreflex function and sympathetic output (22,26).…”

“…Interestingly, a population of AVP-expressing neurons project from the PVN to the hindbrain and spinal cord and appear to be involved in the regulation of sympathetic nervous activity (reviewed in Refs. 1,10,52), suggesting a possible AVP-mediated cross-talk between these two mechanisms.…”

Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor

“…Approximately 10 years ago, co-localization studies using electron microscopic dual immunolabeling of the AT2R and AVP indicated for the first time that there is a co-localization of AT2R and AVP containing neurons in the PVN [44]. Since the PVN is the main area of AVP synthesis, this observation pointed to a role of the AT2R in the control of AVP generation.…”

“…Since the PVN is the main area of AVP synthesis, this observation pointed to a role of the AT2R in the control of AVP generation. Interestingly, the authors of this initial study reported localization of AT2R mainly on neuronal processes in the PVN, but not or only very rarely on soma [44]. The same pattern was found by our group using the AT2R-eGFP-BAC-transgenic reporter-mouse: AT2R-positive, fluorescent green staining was not detectable on the soma of AVP neurons within the PVN, but on processes and nerve terminals arising from AT2R-positive cell bodies in the peri-PVN area, which extended into the PVN and synapsed onto AVP neurons [17,19].…”